The long term goals of this project are to elucidate the molecular and cellular bases for certain toxicant-induced neuropathies. The high degree of specialization of different cell types in the nervous system suggests that specialized metabolic features might be the target for certain neurotoxic compounds. we will pursue this hypothesis by study of the metabolic consequences of exposure to tellurium, a metabolic insult which produces demyelination of the peripheral nervous system (PNS) in weanling rats. This pathology is, in large part, a consequence of the fact that tellurium exposure causes inhibition of the biosynthesis of cholesterol, a major component of the myelin sheath. An early aim is to define, at the molecular level, the mechanism by which tellurium exposure results in inhibition of squalene epoxidase, an enzyme in the pathway of cholesterol synthesis. Tellurium feeding initially induces a systemic block in cholesterol synthesis - why is PNS demyelination and its functional consequences the primary observed pathology? Is it because there is a mechanism for coordinate regulation of synthesis of different protein and lipid components of the myelin membrane, and this mechanism is disrupted by an imbalanced supply of precursors? Specifically, is lack of newly synthesized cholesterol itself sufficient to downregulate some expression of genes for myelin proteins, or alteratively is it breakdown of myelin (secondary to lack of cholesterol) that turns off this gene expression. In this context we will study the steady-state levels of expression of messenger RNA (mRNA) for myelin specific-proteins, such as the major PNS myelin protein P0, for proteins involved in other aspects of Schwann-cell differentiation and dedifferentiation, and for enzymes in the cholesterol biosynthetic pathway, such as hydroxy-methylglutaryl-coenzyme A reductase. Information obtained concerning the relationship between demyelination and the changes in gene expression undergone by the Schwann cell should be relevant to understanding other demyelinating disorders. An extension of the above studies is to test an hypothesis that cells which are the primary target of a particular toxicant can be identified by analysis of transcription of genes specific for highly differentiated functions of these cells. In this context, probing for message for myelin- specific proteins will test for perturbation of function of Schwann cells, while probes for neuronal function will include assay of MRNA for neurofilament protein and for other proteins related to axon structure and function. For example, if the level of mRNA for a myelin protein, P0, is assayed in sciatic nerve and message for neurofilament protein is assayed in the ganglion, we expect tellurium exposure will initially decrease the former while exposure to the axonopathy-inducing agent, isoniazid, will initially alter the latter.